The disclosed subject matter relates to biological ion channel interfaces, including techniques for interfacing biological ion channels with integrated CMOS amplifiers.
Ion channel proteins can generally be found in the cellular membranes of living things. Certain functions of ion channels, including sensing, signaling and energetics, can have important applications, for example and without limitation, to drug discovery. Yet, certain characteristics of ion channels, including the stochastic behavior and delicate structure of ion channels, can present challenges, for example in understanding some of the biomolecular mechanisms and dynamics of channel gating, as well as in reliably utilizing isolated ion channels for biotechnology platforms, including nanopore DNA sequencing.
Ion channels can be analyzed using patch-clamp techniques. Furthermore, biophysical studies of some ion channels can utilize in vitro planar reconstituted lipid bilayers as model cell membranes. Reconstituted bilayers can be suitable at least because they have a chemical makeup that can be well-controlled, generally involve no live cells and can be measured outside physiological conditions, and have a planar geometry suitable for electrochemical measurements.
Electronic measurements of ion channels in both patch-clamp and planar bilayer experiments can be made with voltage-clamp amplifiers, which can measure the ionic current through a lipid membrane while applying an electrochemical potential through electrodes. Single-channel conductance can vary between types of ion channels, but generally have nanoscale dimensions producing currents on the order of picoamperes or less. These relatively weak signals can approach the noise floor of typical electronic amplifiers, and single-channel recordings can generally be constrained in both amplitude and temporal resolution by low signal-to-noise ratios.
Lipid bilayer recordings can have high-frequency noise, which can be a function of experimental capacitances. The equivalent input voltage noise of a voltage-clamp amplifier νn (V Hz−1/2) can produce noise currents through input capacitances (ΣC), with a root-mean squared amplitude that can be represented as:
                              I          RMS                =                                            2              ⁢                                                          ⁢              π                                      3                                ⁢                      B                          3              2                                ⁢                      v            n                    ⁢                      ∑            C                                              (        1        )            where B can represent the measurement bandwidth. One capacitance in lipid bilayer experiments can be that of the lipid membrane itself (CM), and lipid bilayers, which can be a few nanometers thick, can have specific capacitance on the order of 0.5 μF/cm2. Circular planar bilayers diameters ranging from 1 μm-200 μm can thus have CM ranging from 4 fF to 80 pF.
However, there remains an opportunity for improved biological ion channels with reduced parasitic capacitance in biological ion channel recordings and can provide multiple independent recordings on a single chip with improved signal bandwidths.